Joseph A. Markenson

A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.

BACKGROUND Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown. METHODS We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. RESULTS As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate. CONCLUSIONS As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.

Concomitant Leflunomide Therapy in Patients with Active Rheumatoid Arthritis despite Stable Doses of Methotrexate: A Randomized, Double-Blind, Placebo-Controlled Trial

Context Several disease-modifying antirheumatic drugs (DMARDs) slow disease progression in patients with rheumatoid arthritis. Many experts prefer methotrexate, although trials do not uniformly show that it is superior to other DMARDs. It is not known whether combining methotrexate with a second DMARD is better than prescribing methotrexate alone. Contribution This 24-week, randomized, double-blind, placebo-controlled trial shows that leflunomide added to ongoing stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis improves clinical outcomes compared with methotrexate alone. Cautions Some adverse effects, such as diarrhea, were more common with combination therapy. All patients receiving DMARD therapy need close monitoring for toxicities. The Editors Rheumatoid arthritis has considerable societal costs (1-5). Many patients with rheumatoid arthritis become disabled within a few years of disease onset (4, 5). Methotrexate is the standard treatment for rheumatoid arthritis. During the past several years, investigators have found that some disease-modifying antirheumatic drugs can increase the efficacy of methotrexate monotherapy (6-9). Methotrexate is an antimetabolite and immunomodulator that affects many intracellular metabolic pathways of purine metabolism (10). The precise intracellular biochemical pathway responsible for the observed clinical benefits of methotrexate in the treatment of rheumatoid arthritis is still the subject of some debate (11), but methotrexate is thought to act primarily on purine pathways of cellular metabolism (10). Leflunomide (Arava, Aventis Pharmaceuticals, Bridgewater, New Jersey) also has antimetabolic effects, inhibiting pyrimidine intracellular pathways (12). Leflunomide has been shown to be effective for rheumatoid arthritis in double-blind, placebo-controlled trials (13, 14). Given the diverse intracellular pathways affected by both drugs, the combination of leflunomide and methotrexate has the potential for biochemical synergy. The possibility of increased benefits should be weighed against the possible toxicities of this combination. Abnormal aminotransferase levels have been seen with both methotrexate (15) and leflunomide (14) monotherapy in patients with rheumatoid arthritis. In a small open study, we previously observed that the combination of methotrexate and leflunomide led to considerable clinical improvements and reversible elevations in aminotransferase levels (16). We therefore sought to determine whether similar results could be achieved in a large, double-blind investigation of the combination of these two antimetabolic agents. Methods Patients The study sample consisted of 263 patients who had rheumatoid arthritis as defined by American College of Rheumatology (ACR) criteria (17). Patients were 18 to 75 years of age and were receiving stable dosages of methotrexate (15 to 20 mg/wk, or 10 to 15 mg/wk if this was the maximum tolerated dose). Patients were recruited from active outpatient practice centers, and study participants were approached without a particular schema. Eligible patients had active rheumatoid arthritis despite at least 6 months of methotrexate therapy, including stable dosage for at least 8 weeks. Patients with active rheumatoid arthritis were defined as meeting three of the following criteria on two different evaluations, 7 to 21 days apart: at least nine tender joints, at least six swollen joints, at least 45 minutes of morning stiffness, and an erythrocyte sedimentation rate of at least 28 mm/h. Previous disease-modifying antirheumatic drugs, not including ongoing methotrexate, had failed in 11 patients. Patients receiving corticosteroids were required to have been taking a stable daily dose of 10 mg or less for at least 30 days before study drug administration, and the corticosteroid dose was required to remain constant throughout the study. Complete exclusion criteria are listed in Appendix Table 1. Study Design The 24-week, randomized, double-blind, placebo-controlled study, with evaluations occurring at 4-week intervals (Figure 1), was conducted in 20 centers in the United States and Canada between September 1998 and June 2000. The primary objective was to evaluate the efficacy and safety of adding leflunomide or placebo to stable methotrexate therapy in patients with active rheumatoid arthritis. All participants provided written consent, and the institutional review board at each center approved the protocol. Figure 1. Patient eligibility, randomization, assignment, and discontinuation. Include no wish to continue in study, poor adherence to treatment, protocol violation, and moving away from the study area. A randomization schedule, generated by and stored with Quintiles, Inc., Kansas City, Missouri, was used to assign sequential numbers to randomly allocated treatment codes. Randomization was done by using the Aventis standard random-code generator. Investigators allocated numbers to patients, beginning with the lowest available number. Quintiles, Inc., packaged and labeled the study medication. The randomization code used was concealed from investigators and patients throughout the study. Randomization was stratified by center. A set of 500 random numbers was generated, with treatment groups randomly assigned in a balanced manner (1:1 ratio) within each block of four consecutive random numbers (block size, 4). A set of these blocks was then sent to each investigative center. This method is identical to stratification by center because centers are balanced with respect to treatment assignment. Patients were randomly assigned to receive leflunomide, 100 mg/d, for 2 days followed by 10 mg/d or matching placebo. If substantial adverse events occurred, this dose could be reduced to 10 mg every other day. If 10 mg/d was tolerated but active disease, as defined earlier, was still present at week 8 or thereafter, an increase to 20 mg of leflunomide or matching placebo per day was required. If substantial adverse events occurred while the patient was taking 20 mg of the study drug per day, a one-time dose reduction to 10 mg/d was allowed at the discretion of the investigator. At least 1 mg of folate supplementation per day was mandated by the protocol. Adherence to study medication, assessed at each visit by tablet counts (actual number of tablets returned compared with number expected to be returned), was similar in the two groups. The mean adherence for all patients in the intention-to-treat sample was 98.0% (98.5% for those receiving placebo and 97.4% for those receiving leflunomide). In the placebo group and leflunomide group, respectively, 90.2% (120 of 133 patients) and 87.7% (114 of 130 patients) had adherence rates of 80% to 120%. Measurement of Efficacy The primary efficacy variable was the rate at which the intention-to-treat sample achieved 20% improvement in ACR criteria (ACR20) at the end of the study. To be classified as having achieved ACR20, patients were required to complete 24 weeks of treatment and meet ACR20 response criteria at end of the study (13). The ACR20 criteria were developed to define improvement in rheumatoid arthritis (18). Clinical improvement is indicated by 20% improvement in tender and swollen joint counts and 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, pain intensity, physical function or disability measure, and level of acute-phase reactant (19). All ACR assessments were performed by the investigators, and the same assessor performed all analyses throughout the study whenever possible to increase the reliability of the assessment. Patients who discontinued therapy before the end of week 24 or for whom data were insufficient to assess ACR20 response at week 24 were classified as nonresponders for the primary analysis. Count of tender joints was based on 68 joint assessments, and count of swollen joints was based on 66 joint assessments. Percentage changes in tender joint and swollen joint counts were based on the number of evaluable joints at a visit. Joints that had been replaced or had been injected with corticosteroids within 4 weeks before the assessment were considered nonevaluable. Secondary outcomes included ACR50 and ACR70 responder rates at week 24 (analyses of responders at study end for the nonprimary efficacy measures). The ACR50 and ACR70 were defined as at least 50% and 70% improvement, respectively, in the same criteria used to calculate ACR20 response. Secondary efficacy variables also included change from baseline to end point in each of the individual components of the ACR response criteria and change from baseline to week 24 in levels of rheumatoid factor. Mean changes from baseline in individual efficacy measures are shown in Appendix Table 2. Measurement of Safety Safety was evaluated by adverse event reports; laboratory assays for changes in hematologic characteristics, blood chemistry, urinalysis, and liver function; and physical examination. Potential adverse events were assessed by using open-ended questions at each study visit. The assessor was blinded to reported toxicities and to any additional information obtained at the visit. The study protocol provided recommendations for dosage change and discontinuation of drug therapy, without unblinding, when patients were found to have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values greater than two times the upper limit of normal. Investigators decreased the dose of the study medication if, on repeated analysis at 72 hours, test values remained greater than two times but less than or equal to five times the upper limit of normal; only one dose adjustment was allowed before discontinuation of therapy with the study drug. Therapy with the study drug was also discontinued in patients with persistent elevations of aminotransferase enzyme levels to more than two times the upper limit of normal on repeated te

Evaluation of the functional status aspects of health-related quality of life of patients with Osteoarthritis treated with celecoxib

Study Objective. To evaluate the functional status of patients with signs and symptoms of osteoarthritis of the knee after treatment with celecoxib compared with placebo and naproxen.

Worldwide trends in the socioeconomic impact and long-term prognosis of rheumatoid arthritis

Rheumatoid arthritis (RA), once considered a benign and nonprogressive disease, is a debilitating condition with serious physical, emotional, and economic consequences. It afflicts approximately 1% of the adult population worldwide; prevalence increases with age, with twice as many women as men affected. In the United States, age, lack of formal education, and lower socioeconomic class correlate with both the incidence and poor prognosis of RA. The patient with RA faces increasing functional disability, the likelihood of work disability within 10 years after the onset of the disease, and a drastic reduction in earnings. Compared with individuals without the disease, patients with RA incur higher medical care costs, increased hospitalization, and a greater number of physician visits. As in the general population, the leading cause of death among patients with RA is cardiovascular disease, and deaths due to malignancy occur at a comparable incidence; however, patients with RA are at greater risk of mortality due to infection, renal disease, respiratory conditions, and gastrointestinal disease. Life expectancy is shorter among patients with RA than in the general population, and survival rates are comparable to those for Hodgkins disease, diabetes mellitus, stroke, and three-vessel coronary artery disease. Efforts must be made to develop improved therapeutic strategies and rehabilitative programs to improve the quality of life of patients with RA.

Mechanisms of chronic pain

Chronic pain differs from acute pain in that it serves no useful function, causes suffering, limits activities of daily living, and increases costs of healthcare payments, disability, and litigation fees. Pain perception begins with activation of peripheral nociceptors and conduction through myelinated A delta and unmyelinated C fibers to the dorsal root ganglion. From here, signals travel via the spinothalamic tract to the thalamus and the somatosensory cortex. Modulation of sensory input (i.e., pain) occurs at many levels. Nociceptors are also neuroeffectors, and transmission can be modulated by their cell bodies, which secrete inflammatory mediators, neuropeptides, or other pain-producing substances. Descending pathways from the hypothalamus, which has opioid-sensitive receptors and is stimulated by arousal and emotional stress, can transmit signals to the dorsal horn that modulate ascending nociceptive transmissions. Modulation to alter the perception of pain also can occur at higher centers (e.g., frontal cortex, midbrain, medulla) by opioids, anti-inflammatory agents, as well as antagonists and agonists of neurotransmitters. This article will review our current knowledge of the mechanisms involved in (1) the transduction of tissue injury or disease signals (nociception and nociceptive receptors); (2) the transmission of signals rostrally to the thalamus and higher nervous system centers (involving perception of the quality, location, and intensity of noxious signals); and (3) the modulation of ascending sensory messages at all levels (periphery, spinal cord, and higher centers).

T cell receptor peptide vaccination in rheumatoid arthritis : A placebo-controlled trial using a combination of Vβ3, Vβ14, and Vβ17 peptides

OBJECTIVE Restricted T cell receptor (TCR) gene usage has been demonstrated in animal models of autoimmune disease and has resulted in the successful use of TCR peptide therapy in animal studies. This clinical trial was undertaken to determine the safety and efficacy of a combination of Vbeta3, Vbeta14, and Vbeta17 TCR peptides in Freunds incomplete adjuvant (IFA) in patients with rheumatoid arthritis (RA). METHODS A double-blind, placebo-controlled, multicenter, phase II clinical trial was undertaken using IR501 therapeutic vaccine, which consists of a combination of 3 peptides derived from TCRs (Vbeta3, Vbeta14, and Vbeta17) in IFA. A total of 99 patients with active RA received either 90 microg (n = 31) or 300 microg (n = 35) of IR501 or IFA alone (n = 33) as a control. The study medication and placebo were administered as a single intramuscular injection (1 ml) at weeks 0, 4, 8, and 20. RESULTS Treatment with IR501 was safe and well tolerated. None of the patients discontinued the trial because of treatment-related adverse events. Efficacy was measured according to the American College of Rheumatology 20% improvement criteria. Using these criteria, patients in both IR501 dosage groups showed improvement in disease activity. In the most conservative analysis used to evaluate efficacy, an intent-to-treat analysis including all patients who enrolled, the 90-microg dosage group showed a statistically significant improvement compared with control patients at the 20-week time point after the third injection. Trends toward improvement were shown in both the 90-microg and the 300-microg dosage groups at week 24 after the fourth injection. CONCLUSION IR501 therapeutic vaccine therapy was safe and well tolerated, immunogenic, and demonstrated clinical improvement in RA patients. Additional clinical trials are planned to confirm and extend these observations.

Persistence with Anti-Tumor Necrosis Factor Therapies in Patients with Rheumatoid Arthritis: Observations from the RADIUS Registry

Objective. To evaluate persistence with anti-tumor necrosis factor (TNF) therapy and predictors of discontinuation in patients with rheumatoid arthritis (RA). Methods. This retrospective analysis used data from RADIUS 1, a 5-year observational registry of patients with RA, to determine time to first- and second-course discontinuation of etanercept, infliximab, and adalimumab. First-course therapy was defined as first exposure to anti-TNF therapy, and second-course therapy was defined as exposure to anti-TNF therapy after the first discontinuation. Kaplan-Meier survival analysis was used to assess persistence, log-rank tests were used to compare therapies, and Cox proportional hazards models were used to assess potential predictors of treatment discontinuation. Results. This analysis included 2418 patients. Mean persistence rates were similar among treatments [first-course: etanercept, 51%; infliximab, 48%; adalimumab, 48% (followup was 54 weeks for etanercept and infliximab and 42 weeks for adalimumab); second-course: 56%, 50%, 46%, respectively (followup was 36 weeks for etanercept and infliximab and 30 weeks for adalimumab)]. Discontinuations of first-course therapy due to ineffectiveness were similar among treatments (etanercept, 19%; infliximab, 19%; adalimumab, 20%) and discontinuations due to adverse events were significantly (p = 0.0006) lower for etanercept than for infliximab (etanercept, 14%; infliximab, 22%; adalimumab, 17%). Predictors from univariable analysis of first- or second-course therapy discontinuation included increased comorbidities (etanercept), female sex (infliximab), Clinical Disease Activity Index > 22 (infliximab), and a Stanford Health Assessment Questionnaire score > 0.5 (adalimumab). Conclusion. In this population, first- and second-course persistence was similar among anti-TNF therapies. First-course discontinuation due to adverse events was lower with etanercept compared with infliximab.

Toxicity of D-penicillamine in rheumatoid arthritis: A report of 63 patients including two with aplastic anemia and one with the nephrotic syndrome

To assess toxicity of D-penicillamine a retrospective chart review was performed on 63 patients with rheumatoid arthritis receiving penicillamine. These patients had a total of 83 courses of therapy. The mean age of patients was 52 years and the mean duration of disease was 10.07 years. Laboratory data showed an increase in hematocrit values from 36 per cent to 40 per cent and a decrease in the erythrocyte sedimentation rate from an average of 50 to 29 mm/hour. The platelet count also decreased with treatment from 394,000 to 267,000/mm3. The over-all complication rate was 53 per cent. Life-threatening complications occurred in two patients including one case of aplastic anemia and one case of nephrotic syndrome. One additional patient was referred with aplastic anemia. Minor complications include rash in 18 per cent, loss of taste in 6 per cent, dyspepsia in 11 per cent, oral ulceration in 7 per cent and proteinuria of less than 3 g/day in 8 per cent. In summary, 53 per cent of the courses of penicillamine were associated with toxicity including one episode of aplastic anemia and one case of nephrotic syndrome. Therapy was stopped due to complications in 39 per cent of the patients in this series.

Rheumatoid Meningitis: A Localized Immune Process

Rheumatoid pachymeningitis is a rare complication of rheumatoid arthritis. This disease was confined to the dura and pia-arachnoid of the lumbar cord in our patient. Her neurologic deficits responded to surgical decompression and corticosteroid therapy. Radiologic evidence and the differences in cell count, protein, and glucose content between lumbar and cisternal cerebrospinal fluid indicate that rheumatoid pachymeningitis can be localized to a discrete region of the central nervous system. Elevated immunoglobulins, IgM and IgG rheumatoid factors, low molecular weight IgM, and immune complexes were found in the cerebrospinal fluid and implicate an immune reaction in the pathogenesis of this disease, which is probably similar to inflammatory processes involving other organs in rheumatoid arthritis.

Real-world utilization of DMARDs and biologics in rheumatoid arthritis: the RADIUS (Rheumatoid Arthritis Disease- Modifying Anti-Rheumatic Drug Intervention and Utilization Study) study

ABSTRACT Objective: Rheumatoid Arthritis (RA) Disease-Modifying Anti-Rheumatic Drug (DMARD) Intervention and Utilization Study (RADIUS) is a unique, real-world, prospective, 5-year, observational study of over 10 000 patients with RA. RADIUS provides a snapshot of use patterns, effectiveness, and safety of DMARDs, biologics, and combination therapies used to manage RA in clinical practice. Research design and methods: Patients with RA requiring a new DMARD or biologic (addition or switch) were eligible for the RADIUS study. Two separate patient cohorts were enrolled; RADIUS 1 patients initiated any new therapy at entry, and RADIUS 2 patients initiated etanercept at entry. Patient demographics and disease activity measures were collected at study entry, and baseline characteristics were summarized for various subgroups. Effectiveness, safety, and patterns of use will be tracked for therapies utilized during the 5‐year study. Results: RADIUS 1 enrolled 4959 patients, and RADIUS 2 enrolled 5102 patients, mostly at community private practices (88%). In RADIUS 1, most patients initiated methotrexate (MTX) monotherapy, followed by MTX in combination with a biologic (e.g. infliximab plus MTX) or other DMARD. In RADIUS 2, most patients initiated etanercept in combination with MTX, followed by etanercept monotherapy. When a new therapy was required, physicians tended to add another therapy versus switching therapies. Patients initiating a biologic had a longer duration of RA and more severe disease compared with patients initiating non-biologic therapy. Conclusions: These real-world data provide evidence of the prescribing practices of rheumatologists in 2001–2003. Future analyses will allow evidence-based comparisons of the long-term safety and effectiveness of DMARDs, biologics, and combination therapies to assist physicians in clinical decision-making.